SUMMARY OF WORK: We have defined the main mammalian base excision repair (BER) pathways in vitro using purified proteins and cell extracts, and we have cloned the human and mouse genes for many of the enzymes, expressed the recombinant proteins in E. coli and insect cells, and prepared cell lines with genetic alterations in each gene. Transgenic mouse models are studied to understand the cellular and tissue requirements for each enzyme. This project includes studies of the cellular role of BER in overall cellular DNA repair, apoptosis, check point control of the cell cycle, mutagenesis, chromosome stability, DNA lesion bypass, cell signaling, DNA replication control, and human and mouse carcinogenesis. In addition, recent studies by several laboratories have suggested that transcription-coupled BER is an important pathway in oxidative damage DNA repair; investigation of this pathway is also underway.